Phase II Trial of Pimasertib Versus Dacarbazine in N-Ras Mutated Cutaneous Melanoma

• ClinicalTrials.gov Identifier: NCT01693068
• Recruitment Status: Completed
• First Posted: September 26, 2012
• Results First Posted: January 5, 2018
• Last Update Posted: January 5, 2018
• Sponsor: EMD Serono
• Collaborator: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): EMD Serono

Tracking Information

• First Submitted Date: September 14, 2012
• First Posted Date: September 26, 2012
• Results First Submitted Date: October 23, 2017
• Results First Posted Date: January 5, 2018
• Last Update Posted Date: January 5, 2018
• Actual Study Start Date: December 5, 2012
• Actual Primary Completion Date: July 4, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 5, 2017)

Progression Free Survival (PFS) [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015) ]

PFS was defined as the duration (in weeks) from randomization until the first progressive disease (PD) observation as assessed by the Investigator according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, or death due to any cause when death occurred within 12 weeks after the last tumor assessment (otherwise censored), whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of the target lesions, taking as reference the smallest sum since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions.

• Original Primary Outcome Measures (submitted: September 21, 2012): Progression-free survival (PFS), defined as the first documentation of objective disease progression, according to Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) [ Time Frame: every 6 weeks up to Cycle 13, then every 12 weeks up to 2 years ]

Current Secondary Outcome Measures (submitted: December 5, 2017)

• Objective Response Rate (ORR) [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015) ]
  ORR was defined as the percentage of subjects with complete response (CR) or partial response (PR) according to RECIST version 1.1 criteria. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters along with absence of new lesions and disease progression in non-target lesions.
• Disease Control Rate (DCR) [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015) ]
  DCR was defined as the percentage of subjects with CR, PR, or stable disease (SD) for greater than (>) 3 months assessed by investigator according to RECIST version 1.1. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than <10 mm. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters along with absence of new lesions and disease progression in non-target lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
• Percentage of Subjects With Progression-free Survival (PFS) at 6 Months [ Time Frame: 6 months ]
  PFS was defined as the duration (in weeks) from randomization until the first progressive disease (PD) observation as assessed by the Investigator according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, or death due to any cause when death occurred within 12 weeks after the last tumor assessment, whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of the target lesions, taking as reference the smallest sum since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions. Percentage of Subjects with PFS at 6 Months were reported.
• Overall Survival (OS) [ Time Frame: From date of randomization until date of death from any cause, assessed up to cut-off date (04-Jul-2015) ]
  OS was defined as the time (in months) from randomization to death due to any cause. Subjects without a death date were to be censored at the minimum of last known date alive, defined as the latest date available on the electronic case report form, and cut-off date.
• Percentage of Subjects With Overall Survival (OS) at 12 Months [ Time Frame: 12 months ]
  OS was defined as the time (in months) from randomization to death due to any cause. Subjects without a death date were to be censored at the minimum of last known date alive, defined as the latest date available on the electronic case report form, and cut-off date. Percentage of Subjects with OS at 12 months were reported.
• Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Total Score (FACT-M TS) at Day 1 of Pre-Specified Cycles and End of Treatment (EOT) [ Time Frame: Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37 and EOT (up to cut-off date [04-Jul-2015]) ]
  QoL assessed using Function Assessment Cancer Therapy-melanoma (FACT-M) assessment tool. This includes 27-item FACT-General (FACT-G) questionnaire which consists of 24 questions;7 relating to physical well-being (PWB),7 relating to social/family well-being (SWB),6 relating to emotional well-being (EWB) and 7 relating to functional well-being (FWB). Also, it includes melanoma-specific subscale consists of 16 questions for Melanoma Subscale (MS) and 8 questions for Melanoma Surgery Scale (MSS).Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Total Score (FACT-M TS) ranges from 0 to 172 and is derived as follows: FACT-M TS= PWB Score + SWB Score + EWB Score + FWB Score + MS Score. Higher scores represent a better quality of life.
• Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Trial Outcome Index (FACT-M TOI) at Day 1 of Pre-Specified Cycles and End of Treatment (EOT) [ Time Frame: Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37 and EOT (up to cut-off date [04-Jul-2015]) ]
  QoL assessed using FACT-M assessment tool. This includes 27-item FACT-G questionnaire which consists of 24 questions; 7 relating to PWB, 7 relating to SWB, 6 relating to EWB and 7 relating to FWB. Also, it includes melanoma-specific subscale consists of 16 questions for MS and 8 questions for the MSS. Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Trial Outcome Index (FACT-M TOI) ranges from 0 to a high of 120 and is derived as: FACT-M TOI = PWB Score + FWB Score +MS Score. Higher scores represent a better quality of life.
• Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death [ Time Frame: Baseline up to cut-off date (04-Jul-2015) ]
  AE was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and up to 33 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs. TEAEs were to be reported separately for dacarbazine, pimasertib and pimasertib (crossover) reporting arms.
• Number of Subjects With Adverse Events (AEs) of Special Interest [ Time Frame: Baseline up to cut-off date (04-Jul-2015) ]
  Adverse events of special interest included ocular retinal vein occlusion, serious retinal detachment or similar retinal abnormality characterized by accumulation of serous fluid in the retina, creatine phosphokinase (CPK) elevation and isoenzyme TEAE of Special Interest (Grade >=2) and acute renal failure (Grade >=2). Subjects were presented under 3 reporting groups: Dacarbazine group: for subjects who received at least 1 dose of dacarbazine; Pimasertib group: for subjects who received at least 1 dose of pimasertib; Pimasertib (Crossover) group: for subjects who were initially randomized and received dacarbazine, but crossed over to pimasertib treatment on progression of their disease.
• Number of Subjects With Clinically Significant Change From Baseline in Laboratory Parameter, Vital Signs, Electrocardiogram (ECG) and Ophthalmologic Findings [ Time Frame: Baseline up to cut-off date (04-Jul-2015) ]
  Subjects were presented under 3 reporting groups: Dacarbazine group: for subjects who received at least 1 dose of dacarbazine; Pimasertib group: for subjects who received at least 1 dose of pimasertib; Pimasertib (Crossover) group: for subjects who were initially randomized and received dacarbazine, but crossed over to pimasertib treatment on progression of their disease.

Original Secondary Outcome Measures (submitted: September 21, 2012)

• Objective response defined as complete or partial tumor response, according to RECIST v.1.1 criteria [ Time Frame: every 6 weeks up to Cycle 13, then every 12 weeks up to 2 years ]
• Disease control defined as the proportion of subjects with complete response, partial response, or stable disease for more than 3 months, according to RECIST v.1.1 criteria [ Time Frame: every 6 weeks up to Cycle 13, then every 12 weeks up to 2 years ]
• Progression-free survival rate at six months from the time of randomization based upon objective disease progression, according to RECIST v.1.1 criteria [ Time Frame: up to 6 months ]
• Overall survival defined as the time from randomization to death from any cause [ Time Frame: every 6 months up to 2 years ]
• Overall survival rate at 12 months from the time of randomization [ Time Frame: up to 12 months ]
• Change in patient-reported Quality of life (assessed by FACT-Melanoma) from baseline assessment to last assessment prior to objective disease progression, according to RECIST v.1.1 [ Time Frame: Day 1 of every cycle up to 2 years ]
• Number of subjects with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and death [ Time Frame: up to 2 years ]
• Clinically significant changes in safety related to National Cancer Institute- Common Toxicity Criteria Version 4.0 (NCI-CTC v 4.0) and abnormal vital signs [ Time Frame: up to 2 years ]
• Plasma pharmacokinetic parameters of pimasertib [ Time Frame: Day 8 and Day 15 of Cycle 1, and Day 1 of Cycle 2 ]
• Gene products and genetic alterations in tumor biopsies [ Time Frame: Day 1 of Cycle 1 ]
• Predictive markers in plasma [ Time Frame: Day 1 of Cycle 1 ]
• Potential genetic variations in genomic deoxyribonucleic acid (gDNA) obtained from Peripheral Blood Mononuclear Cell (PBMC) associated with differences in pharmacokinetic and profile of pimasertib [ Time Frame: Day 1 of Cycle 1 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase II Trial of Pimasertib Versus Dacarbazine in N-Ras Mutated Cutaneous Melanoma
• Official Title: A Multicenter, Open Label, Randomized Phase II Trial of the MEK Inhibitor Pimasertib or Dacarbazine in Previously Untreated Subjects With N-Ras Mutated Locally Advanced or Metastatic Malignant Cutaneous Melanoma
• Brief Summary: This is a Phase 2, multicenter, randomized, controlled, open-label trial of pimasertib versus dacarbazine aimed to confirm the activity of pimasertib in previously untreated subjects with N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma by comparing the progression-free survival (PFS) of subjects treated with either pimasertib or dacarbazine and by getting a better understanding of the efficacy, safety, pharmacogenomics (PGx) and their relationship with pimasertib exposure.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: N-Ras Mutated Locally Advanced or Metastasis Malignant Cutaneous Melanoma

Intervention

• Drug: Pimasertib
  Subjects will receive pimasertib orally as monotherapy at a dose of 60 milligram (mg) twice daily continuously. Treatment will consist of repeated 21-day cycles which will continue until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurs first.
  Other Names:

  • MSC1936369B
  • AS703026
• Drug: Dacarbazine
  Subjects will receive dacarbazine intravenously at dose of 1000 milligram per square meter (mg/m^2) of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurs first. Eligible subjects with documented tumor progression on dacarbazine will offer to switch to pimasertib treatment.

Study Arms

• Experimental: Pimasertib
  Intervention: Drug: Pimasertib
• Active Comparator: Dacarbazine
  Intervention: Drug: Dacarbazine

• Publications *: Lebbe C, Dutriaux C, Lesimple T, Kruit W, Kerger J, Thomas L, Guillot B, Braud F, Garbe C, Grob JJ, Loquai C, Ferraresi V, Robert C, Vasey P, Conry R, Isaacs R, Espinosa E, Schueler A, Massimini G, Dreno B. Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover. Cancers (Basel). 2020 Jun 29;12(7):1727. doi: 10.3390/cancers12071727.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 10, 2014): 194
• Original Estimated Enrollment (submitted: September 21, 2012): 184
• Actual Study Completion Date: October 24, 2016
• Actual Primary Completion Date: July 4, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subjects with measurable, histologically or cytologically confirmed, locally advanced or metastatic cutaneous melanoma (stage III c or M1ac) N-Ras mutated. If N-Ras mutational status is unknown at screening, it must be prospectively defined before inclusion. If N-Ras mutational status is already known before screening, it must be retrospectively confirmed after inclusion by the sponsor.
• Tumor lesions amenable to biopsy or available tumor tissue as archival samples.
• Age greater than or equal to (>=) 18 years.
• Has read and understood the informed consent form and is willing and able to give informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments.
• Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For the purposes of this trial, women of childbearing potential are defined as: "All female subjects after puberty unless they are post-menopausal for at least two years, or are surgically sterile".
• Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to, during and four weeks after the last dose of trial medication. Effective contraception is defined as the method of contraception with a failure rate of less than 1% per year. Adequate contraception is defined as follows: two barrier methods or one barrier method with a spermicidal or intrauterine device or oral contraception for female partners of male subjects.

Exclusion Criteria:

• Has previous systemic treatment for locally advanced or metastatic cutaneous melanoma (excluding adjuvant treatment).
• Has non-measurable lesions, disease not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1
• Has an Eastern Cooperative Oncology Group performance status (ECOG PS) >1.
• Has bone marrow impairment as evidenced by Hemoglobin <10.0 g/dL, Neutrophil count <1.5 * 10^9/L, platelets <100 * 10^9/L.
• Has renal impairment as evidenced by calculated creatinine clearance <60 mL/min (according to the Cockcroft-Gault formula).
• Has liver function abnormality as defined by total bilirubin >1.5 * Upper Limit of Normal (ULN), or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2.5 * ULN, for subjects with liver involvement AST/ALT >5 * ULN.
• Has significant cardiac conduction abnormalities, including QTc prolongation of >480 milliseconds and/or pacemaker or clinically relevant impaired cardiovascular function.
• Has hypertension uncontrolled by medication
• Has retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis, or history of retinal vein occlusion (RVO) or any eye condition that would be considered a risk factor for RVO (e.g., uncontrolled glaucoma or ocular hypertension).
• Has known active central nervous system (CNS) metastases unless previously radiotherapy treated, stable by CT scan for at least 3 months without evidence of cerebral edema and no requirements for corticosteroids or anticonvulsants.
• History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease, or conditions that may hamper compliance and/or absorption of the tested product.
• Known human immunodeficiency virus (HIV) positivity, active hepatitis C, or active hepatitis B.
• Has undergone surgical intervention within 28 days from Day 1 of trial drug treatment.
• Has received extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from Day 1 of trial drug treatment.
• Has history of any other significant medical disease such as major gastric or small bowel surgery, recent drainage of significant volumes of ascites or pleural effusion or has a psychiatric condition that might impair the subject well-being or preclude full participation in the trial.
• Has known hypersensitivity to dacarbazine.
• Is a pregnant or nursing female.
• Participated in another clinical trial within the past 28 days.
• Has creatine phosphokinase (CPK) level at baseline National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade >=2 (i.e > 2.5 * ULN), and/or has a previous history of myositis or rhabdomyolysis.
• Is suitable for treatment with an approved B-Raf inhibitor (exclusion criteria implemented in German amendment only).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, France, Germany, Israel, Italy, Netherlands, New Zealand, South Africa, Spain, Sweden, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT01693068
• Other Study ID Numbers: EMR 200066-007; 2012-002669-37 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: EMD Serono
• Original Responsible Party: Same as current
• Current Study Sponsor: EMD Serono
• Original Study Sponsor: Same as current
• Collaborators: Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Study Director; EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany

• PRS Account: EMD Serono
• Verification Date: December 2017